Chronic Heart Failure, Echocardiogram, History of Chronic Heart Failure, Left Ventricular Ejection Fraction, Left Ventricular Systolic Dysfunction, Modified Release Oral Formulation, Pharmacokinetics
Conditions
Keywords
Pharmacokinetics, Omecamtiv mecarbil, AMG 423, Double-blind, Randomized, Placebo-controlled, Oral forumlation, CK-1827452, Cardiac myosin activator
Brief summary
The primary objectives of this study are (i) to select an oral modified release (MR) formulation and dose of omecamtiv mecarbil for chronic twice daily (BID) dosing in adults with heart failure and left ventricular systolic dysfunction and (ii) to characterize its pharmacokinetics (PK) over 20 weeks of treatment.
Detailed description
Omecamtiv mecarbil (AMG 423, CK-1827452) is a novel small molecule that increases cardiac contractility by selectively and directly activating the enzymatic domain of cardiac myosin heavy chain, the force-generating motor protein of the cardiac sarcomere. This is a randomized, placebo-controlled, multicenter, phase 2 study, consisting of a dose escalation phase to select 1 of 3 omecamtiv mecarbil oral formulations in 2 dose escalation cohorts, followed by an expansion phase to evaluate 20 weeks of administration of the selected omecamtiv mecarbil formulation at 2 target dose levels, compared with placebo. This study was conducted by Amgen as the IND holder, with Cytokinetics as a collaborator. Due to the termination of the collaboration agreement between Amgen and Cytokinetics in May 2021 and subsequent transfer of the omecamtiv mecarbil IND from Amgen to Cytokinetics, Cytokinetics is now listed as the sponsor.
Interventions
DRUGOmecamtiv Mecarbil Matrix F1 Formulation
Modified release tablets for oral administration
DRUGOmecamtiv Mecarbil Matrix F2 Formulation
Modified release tablets for oral administration
DRUGPlacebo
Modified release tablets matching to omecamtiv mecarbil
DRUGOmecamtiv Mecarbil Swellable Core Technology F2
Modified release tablets for oral administration
Sponsors
Cytokinetics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* History of chronic heart failure (HF), defined as requiring treatment for HF for a minimum of 4 weeks prior to screening * Treated with stable, optimal pharmacological therapy for ≥ 4 weeks * History of left ventricular ejection fraction (LVEF) ≤ 40% * Elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP)
Exclusion criteria
* Severe uncorrected valvular heart disease * Hospitalization within 30 days prior to enrollment * Hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease * Acute myocardial infarction, unstable angina or persistent angina at rest within 30 days prior to randomization * Systolic blood pressure \> 160 mmHg or \< 90 mmHg or diastolic blood pressure \> 90 mmHg * Total bilirubin ≥ 2 x upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 x ULN * Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73m\^2
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours, and 7 days post-dose. |
| Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours, and 7 days post-dose. |
| Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7 | Day 7 at predose |
| Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil | Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose |
| Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Predose (before morning dose) at weeks 2, 8, 12, 16, and 20 |
| Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil | Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase. | An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant, including worsening of a preexisting medical condition. The event does not necessarily have a causal relationship with study treatment. Laboratory value changes that required treatment or adjustment in current therapy were considered adverse events. Each adverse event was graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE), where Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, and Grade 4 = life-threatening AE. A serious adverse event is defined as an adverse event that met at least 1 of the following serious criteria: * fatal * life threatening * required in-patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event |
| Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20 | Baseline and week 20 | Systolic ejection time was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. |
| Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | From first dose of study drug until 4 weeks after last dose; treatment duration was 20 weeks in the expansion phase. | An adverse event is defined as any untoward medical occurrence in a clinical trial participant, including worsening of a preexisting medical condition. The event does not necessarily have a causal relationship with study treatment. Laboratory value changes that required treatment or adjustment in current therapy were considered adverse events. Each adverse event was graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE), where Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, and Grade 4 = life-threatening AE. A serious adverse event is defined as an adverse event that met at least 1 of the following serious criteria: * fatal * life threatening * required in-patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event |
| Expansion Phase: Change From Baseline in Stroke Volume at Week 20 | Baseline and week 20 | Stroke volume was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. |
| Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20 | Baseline and week 20 | LVESD was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. |
| Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20 | Baseline and week 20 | LVEDD was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. |
| Expansion Phase: Change From Baseline in Heart Rate at Week 20 | Baseline and week 20 | Heart rate was measured using electrocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. |
| Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20 | Baseline and week 20 | Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. |
Countries
Australia, Belgium, Bulgaria, Canada, Czechia, Germany, Hungary, Italy, Lithuania, Netherlands, Poland, United Kingdom, United States
Participant flow
Recruitment details
Participants with chronic heart failure treated with stable, optimal pharmacological therapy for ≥ 4 weeks were enrolled from February 2013 to March 2015 at 86 centers in 13 countries in Europe, Australia, and North America. The study consisted of a dose-escalation phase to select 1 of 3 omecamtiv mecarbil (OM) oral formulations in 2 dose cohorts, and an expansion phase to evaluate 20 weeks of treatment with the selected formulation at 2 target dose levels, compared with placebo.
Pre-assignment details
In each of the dose-escalation cohorts participants were randomized equally to receive 1 of the 3 formulations of OM or placebo. In the expansion phase participants were randomized equally to receive 25 mg oral OM twice daily (fixed-dose group), 25 mg oral OM twice daily titrated up to 50 mg twice daily (pharmacokinetic-titration group), or oral placebo. Randomization in both phases was stratified by presence or absence of atrial fibrillation/flutter.
Participants by arm
| Arm | Count |
|---|---|
| Dose-escalation Cohort 1: Placebo Participants received placebo tablets twice a day (BID) for 7 days. | 11 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. | 11 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. | 14 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. | 13 |
| Dose-escalation Cohort 2: Placebo Participants received placebo tablets twice a day for 7 days. | 10 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. | 11 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. | 12 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days. | 14 |
| Expansion Phase: Placebo Participants received placebo tablets twice a day for 20 weeks. | 149 |
| Expansion Phase: Omecamtiv Mecarbil 25 mg Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. | 150 |
| Expansion Phase: OM PK-based Titration Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day. At week 8 the dose escalated to 50 mg twice a day if the week 2 predose plasma concentration of OM was less than the predefined cutoff of 200 ng/mL. | 149 |
| Total | 544 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 1 | 3 |
| Overall Study | Decision by sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 3 | 7 |
Baseline characteristics
| Characteristic | Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose-escalation Cohort 2: Placebo | Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose-escalation Cohort 1: Placebo | Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Expansion Phase: Placebo | Expansion Phase: Omecamtiv Mecarbil 25 mg | Expansion Phase: OM PK-based Titration | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 67.7 years STANDARD_DEVIATION 11.4 | 65.3 years STANDARD_DEVIATION 8.8 | 66.7 years STANDARD_DEVIATION 8.7 | 62.1 years STANDARD_DEVIATION 9.3 | 65.1 years STANDARD_DEVIATION 7 | 63.8 years STANDARD_DEVIATION 11.6 | 66.5 years STANDARD_DEVIATION 4.6 | 64.3 years STANDARD_DEVIATION 11.5 | 63.7 years STANDARD_DEVIATION 9.7 | 62.8 years STANDARD_DEVIATION 10.2 | 62.7 years STANDARD_DEVIATION 11.7 | 63.4 years STANDARD_DEVIATION 10.4 |
| Age, Customized 18 - 64 years | 4 Participants | 7 Participants | 5 Participants | 5 Participants | 6 Participants | 5 Participants | 3 Participants | 6 Participants | 82 Participants | 81 Participants | 76 Participants | 280 Participants |
| Age, Customized 65 - 74 years | 4 Participants | 4 Participants | 6 Participants | 5 Participants | 4 Participants | 4 Participants | 8 Participants | 5 Participants | 46 Participants | 52 Participants | 50 Participants | 188 Participants |
| Age, Customized 75 - 84 years | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 3 Participants | 21 Participants | 17 Participants | 23 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 7 Participants | 4 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 14 Participants | 12 Participants | 9 Participants | 11 Participants | 11 Participants | 11 Participants | 14 Participants | 147 Participants | 143 Participants | 145 Participants | 527 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 11 Participants | 5 Participants | 8 Participants | 34 Participants |
| Race/Ethnicity, Customized Mixed Race | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 14 Participants | 12 Participants | 10 Participants | 8 Participants | 11 Participants | 7 Participants | 12 Participants | 136 Participants | 142 Participants | 140 Participants | 502 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 1 Participants | 3 Participants | 3 Participants | 4 Participants | 2 Participants | 2 Participants | 30 Participants | 23 Participants | 24 Participants | 97 Participants |
| Sex: Female, Male Male | 9 Participants | 11 Participants | 12 Participants | 7 Participants | 8 Participants | 8 Participants | 9 Participants | 12 Participants | 119 Participants | 127 Participants | 125 Participants | 447 Participants |
| Stratification Factor - Atrial Fibrillation/Flutter at Randomization No | 11 Participants | 11 Participants | 11 Participants | 10 Participants | 10 Participants | 10 Participants | 11 Participants | 11 Participants | 117 Participants | 118 Participants | 117 Participants | 437 Participants |
| Stratification Factor - Atrial Fibrillation/Flutter at Randomization Yes | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 32 Participants | 32 Participants | 32 Participants | 107 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 11 | 2 / 10 | 5 / 14 | 6 / 13 | 1 / 10 | 8 / 11 | 3 / 11 | 4 / 14 | 48 / 149 | 51 / 150 | 48 / 146 |
| serious Total, serious adverse events | 0 / 11 | 0 / 10 | 1 / 14 | 0 / 13 | 0 / 10 | 2 / 11 | 0 / 11 | 1 / 14 | 30 / 149 | 36 / 150 | 32 / 146 |
Outcome results
Primary
Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil
Time frame: Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil | 2030 ng*hr/mL | Standard Deviation 658 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil | 2000 ng*hr/mL | Standard Deviation 1020 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil | 1740 ng*hr/mL | Standard Deviation 586 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil | 5070 ng*hr/mL | Standard Deviation 1060 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil | 5010 ng*hr/mL | Standard Deviation 1160 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil | 6550 ng*hr/mL | Standard Deviation 2340 |
Primary
Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
Time frame: Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours, and 7 days post-dose.
Population: The pharmacokinetic analysis set (PKAS) included all randomized participants who received at least 1 dose of OM and had at least 1 evaluable OM PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 193 ng/mL | Standard Deviation 58.8 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 201 ng/mL | Standard Deviation 94.4 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 171 ng/mL | Standard Deviation 53.8 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 492 ng/mL | Standard Deviation 115 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 502 ng/mL | Standard Deviation 138 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 601 ng/mL | Standard Deviation 204 |
Primary
Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7
Time frame: Day 7 at predose
Population: Pharmacokinetic analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7 | 157 ng/mL | Standard Deviation 63.7 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7 | 137 ng/mL | Standard Deviation 56.8 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7 | 134 ng/mL | Standard Deviation 54.7 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7 | 376 ng/mL | Standard Deviation 170 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7 | 395 ng/mL | Standard Deviation 108 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7 | 476 ng/mL | Standard Deviation 234 |
Primary
Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
Time frame: Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours, and 7 days post-dose.
Population: Pharmacokinetic analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 3.9 hours | Standard Deviation 4.4 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 2.0 hours | Standard Deviation 1.2 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 4.2 hours | Standard Deviation 1.9 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 2.6 hours | Standard Deviation 2.4 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 2.2 hours | Standard Deviation 1.8 |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) | 4.6 hours | Standard Deviation 2.3 |
Primary
Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil
Time frame: Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose.
Population: Pharmacokinetic analysis set with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil | Week 2 | 212 ng/mL | Standard Deviation 70.4 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil | Week 12 | 200 ng/mL | Standard Deviation 71.1 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil | Week 2 | 212 ng/mL | Standard Deviation 81 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil | Week 12 | 318 ng/mL | Standard Deviation 129 |
Primary
Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing
Time frame: Predose (before morning dose) at weeks 2, 8, 12, 16, and 20
Population: Pharmacokinetic analysis set with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Week 8 | 156 ng/mL | Standard Deviation 69.1 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Week 16 | 155 ng/mL | Standard Deviation 69 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Week 12 | 165 ng/mL | Standard Deviation 67.9 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Week 20 | 149 ng/mL | Standard Deviation 71.2 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Week 2 | 174 ng/mL | Standard Deviation 62.2 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Week 20 | 239 ng/mL | Standard Deviation 118 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Week 2 | 179 ng/mL | Standard Deviation 68.8 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Week 8 | 161 ng/mL | Standard Deviation 74.4 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Week 12 | 263 ng/mL | Standard Deviation 116 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing | Week 16 | 240 ng/mL | Standard Deviation 120 |
Secondary
Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant, including worsening of a preexisting medical condition. The event does not necessarily have a causal relationship with study treatment. Laboratory value changes that required treatment or adjustment in current therapy were considered adverse events. Each adverse event was graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE), where Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, and Grade 4 = life-threatening AE. A serious adverse event is defined as an adverse event that met at least 1 of the following serious criteria: * fatal * life threatening * required in-patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event
Time frame: From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase.
Population: Participants randomized in the dose-escalation phase who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 4 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 1 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 2 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 1 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 1 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 0 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 1 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 6 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 6 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 1 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 1 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 1 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 9 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 5 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 2 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 2 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 2 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 3 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 1 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 5 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 1 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 0 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 1 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 1 Participants |
| Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
Secondary
Expansion Phase: Change From Baseline in Heart Rate at Week 20
Heart rate was measured using electrocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
Time frame: Baseline and week 20
Population: The full analysis set included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Change From Baseline in Heart Rate at Week 20 | 0.57 bpm | Standard Error 0.79 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Change From Baseline in Heart Rate at Week 20 | -0.77 bpm | Standard Error 0.79 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Change From Baseline in Heart Rate at Week 20 | -2.40 bpm | Standard Error 0.81 |
p-value: 0.217795% CI: [-3.47, 0.79]Repeated Measures
p-value: 0.00795% CI: [-5.12, -0.81]Repeated Measures
Secondary
Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20
LVEDD was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
Time frame: Baseline and week 20
Population: The full analysis set included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20 | 0.089 cm | Standard Error 0.038 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20 | 0.023 cm | Standard Error 0.038 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20 | -0.040 cm | Standard Error 0.04 |
p-value: 0.189995% CI: [-0.166, 0.033]Repeated Measures
p-value: 0.012895% CI: [-0.231, -0.028]Repeated Measures
Secondary
Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20
LVESD was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
Time frame: Baseline and week 20
Population: The full analysis set included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20 | -0.242 cm | Standard Error 0.043 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20 | -0.322 cm | Standard Error 0.044 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20 | -0.421 cm | Standard Error 0.045 |
p-value: 0.173295% CI: [-0.194, 0.035]Repeated Measures
p-value: 0.002795% CI: [-0.295, -0.062]Repeated Measures
Secondary
Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20
Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
Time frame: Baseline and week 20
Population: The full analysis set included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20 | 502 pg/mL | Standard Error 257 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20 | -319 pg/mL | Standard Error 257 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20 | -468 pg/mL | Standard Error 262 |
p-value: 0.020595% CI: [-1516, -127]Repeated Measures
p-value: 0.006995% CI: [-1672, -268]Repeated Measures
Secondary
Expansion Phase: Change From Baseline in Stroke Volume at Week 20
Stroke volume was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
Time frame: Baseline and week 20
Population: The full analysis set included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Change From Baseline in Stroke Volume at Week 20 | -1.05 mL | Standard Error 1.18 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Change From Baseline in Stroke Volume at Week 20 | 3.53 mL | Standard Error 1.16 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Change From Baseline in Stroke Volume at Week 20 | 2.58 mL | Standard Error 1.19 |
p-value: 0.003695% CI: [1.5, 7.65]Repeated Measures
p-value: 0.021795% CI: [0.53, 6.72]Repeated Measures
Secondary
Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20
Systolic ejection time was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
Time frame: Baseline and week 20
Population: The full analysis set (FAS) included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20 | 0.0000 seconds | Standard Error 0.0025 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20 | 0.0112 seconds | Standard Error 0.0024 |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20 | 0.0250 seconds | Standard Error 0.0026 |
p-value: 0.000795% CI: [0.0047, 0.0176]Repeated Measures
p-value: <0.000195% CI: [0.0184, 0.0315]Repeated Measures
Secondary
Expansion Phase: Number of Participants With Treatment-emergent Adverse Events
An adverse event is defined as any untoward medical occurrence in a clinical trial participant, including worsening of a preexisting medical condition. The event does not necessarily have a causal relationship with study treatment. Laboratory value changes that required treatment or adjustment in current therapy were considered adverse events. Each adverse event was graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE), where Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, and Grade 4 = life-threatening AE. A serious adverse event is defined as an adverse event that met at least 1 of the following serious criteria: * fatal * life threatening * required in-patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event
Time frame: From first dose of study drug until 4 weeks after last dose; treatment duration was 20 weeks in the expansion phase.
Population: All participants randomized in the expansion phase who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 30 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 62 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAEs leading to discontinuation of study drug | 12 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 4 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 91 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 34 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 5 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 1 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 36 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 8 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 28 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAEs leading to discontinuation of study drug | 8 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 60 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 92 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 3 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 95 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 2 | 61 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 3 | 31 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAE Grade ≥ 4 | 11 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 32 Participants |
| Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 | Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | TEAEs leading to discontinuation of study drug | 12 Participants |